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Iatrogenic ureteral injury (IUI) can complicate minimally invasive and open abdominopelvic surgery. The incidence of IUI is low and dependent on the type of surgery (< 10 %), but it is associated with high morbidity. Therefore, intraoperative visualization of the ureter is critical to reduce the incidence of IUI, and some methodologies for ureter visualization have been developed. Amongst these, near-infrared fluorescence (NIRF) visualization is thought to bring an advantage with real-time retroperitoneal visualization through the retroperitoneum. We investigated an indocyanine green (ICG) derivative, ASP5354, which emits NIRF at 820 nm when exposed to near-infrared light at a wavelength of 780 nm, in a rodent and porcine model. Wistar rats and Gottingen minipigs under anesthesia were laparotomized and then administered ASP5354 chloride intravenously at dose of 0.03 and 0.3 mg/kg for rats and 0.001 and 0.01 mg/kg for minipigs, respectively. Videos of the abdominal cavity in minipigs were taken using a near-infrared fluorescent camera (pde-neo) and assessed visually by three independent clinicians. Toxicological evaluation was demonstrated with cynomolgus monkeys. The proportion of animals whose ureters were visible up to 3 h after administration of ASP5354 chloride were 33 % at 0.001 mg/kg and 100 % at 0.01 mg/kg, respectively. In a toxicological study in cynomolgus monkeys, ASP5354 chloride demonstrated no significant toxicity, suggesting that 0.01 mg/kg provides an optimal dose when used clinically and could allow for ureter visualization during routine surgical procedures. The dose of 0.01 mg/kg provided an optimal dose for ureter visualization up to 3 h after administration. ASP5354 shows promise for ureter visualization during abdominopelvic surgery, which may potentially lower the risk of IUI.

We demonstrated that p- and n-type activation layers can be formed in Si films by laser doping with H3PO4 solution and Al2O3 sol coating. The phosphorus and aluminum concentrations at the laser doped region were found to be over 1019 cm-3 in Si films. In addition, generations of the activation carriers for n- and p-type layers were confirmed by Hall effects measurement. In this study, the characteristic of CMOS invertors fabricated by laser doping are presented.

This article investigates the way in which The Handmaiden (2017), a South-Korean adaptation of Sarah Waters's Fingersmith (2002), provides a way of considering neo-Victorian adaptation in the globalised context. Although set in Korea under Japanese colonial rule in the 1930s, the film indirectly refers in the background to traces of Victorian Britain. Replacing Fingersmith's class conflict with the cultural conflict between Japan and Korea, The Handmaiden represents the intricate process of cultural colonisation. Korean society in the 1930s is depicted in the film as doubly indebted to Victorian British and Japanese culture, for Japan modernised the country through absorbing Western culture in the late nineteenth century. The influence of Victorian Britain, a looming presence in the background of The Handmaiden, reveals how Victorian culture resonates in a country distant from Britain in a different time period. The Handmaiden serves to globalise the definition of the term ‘(neo)Victorian’ by shedding light on the influence of Victorian Britain in the Korean society of the 1930s. The Handmaiden's unique way of bringing together Victorian Britain and the regional politics of 1930s Northeast Asia serves to widen the range of neo-Victorian imaginations.

An organic build-up film is used as the substrate material for a semiconductor multi-die package. However, the miniaturization of the organic build-up film process by the commonly used 355 nm UV laser has almost reached the limit due to its long wavelength. Therefore, to miniaturize the build-up film process, it is necessary to use an excimer laser with a shorter wavelength than the UV laser. In addition, the high photon energy due to the short wavelength of the excimer laser means the thermal effect of the material can be reduced by direct photon absorption. We have developed several types of DUV excimer lasers. One of them is a high power 248 nm excimer laser with free spectrum operation. The 248 nm excimer laser can be applied to the process of organic materials for semiconductor packages. We are developing the processing of organic materials by 248 nm excimer laser. The organic materials are processed directly by the irradiation using the mask by 248 nm excimer laser. We report microdrilling processability of less than 20 μm diameter for a build-up film using a 248 nm excimer laser. The dependence of the taper angle, processing rate on the fluence for various via hole diameters was evaluated for major commercial build-up films. The results of this study indicate the appropriate selection of build-up film material and excimer laser processing fluence to achieve the processing target diameter and taper angle.

In this study, we are developing the process of glass ablation by 248nm excimer to make micro-via to the glass material. The interposer connects many pins between both sides electrically. Therefore, the micro-via to the glass substrate must be needed. However, the micro-via machining to the glass material is difficult because the glass is brittle material. We report microdrilling processability of less than 20um diameter for glass material using a 248nm excimer laser. We also report the investigation result of the dependence of the drilling rate and laser fluence and laser pulse width.

Intraoperative ureter identification helps reduce the risk of ureteral injury. Currently, no suitable agents for real-time ureter visualization are approved. ASP5354 (TK-1) is a novel indocyanine green derivative. In this first-in-human phase 1, double-blind, sequential ascending-dose study, urethral catheters were placed in 6 healthy volunteers who were randomized to single-dose, intravenous ASP5354 0.1 mg (n = 4) or placebo (n = 2). Sequential dose escalations to 0.5-, 2-, 8-, and 24-mg ASP5354 in new cohorts were contingent upon Dose-Escalation Committee approval after review of pharmacokinetic (PK) and safety data. Blood and urine samples were collected over 24 hours following dose administration. Objectives were to assess the safety/tolerability and PK of ASP5354. Treatment-emergent adverse events (TEAEs) were reported in 3 (15%) and 2 (20%) participants in the ASP5354 and placebo groups, respectively. In the former, there were 6 TEAEs (5/6 grade 1-2). One ASP5354 participant experienced grade 3 pyelonephritis, attributed to the catheter. No TEAEs were related to ASP5354. Mean plasma terminal elimination half-life ranged from 2.1 to 3.6 hours, with near complete urinary excretion of unchanged ASP5354 within 24 hours after administration. Linear and dose-proportional PK were observed. These results support further evaluation of ASP5354 at doses up to 24 mg for intraoperative near-infrared fluorescence ureter visualization.

High performance, high speed processing, and miniaturization of electronic devices are advancing, due to the rapid development of highly advanced information society in recent years. Semiconductors continue to be highly integrated according to Moore's law, and semiconductor package substrates are also required to be miniaturized and highly densified. The build-up method is one of the methods for miniaturization and high density of semiconductor package substrates. The build-up method is method of alternately forming insulation layers and conductor layers on both sides of a glass epoxy substrate. In general, an organic build-up film is used for the insulation layers, and a via is formed in the insulation layers by laser processing. However, the miniaturization of the organic build-up film process by the commonly used 355 nm UV laser has almost reached the limit due to its long wavelength. Therefore, to miniaturize the build-up film process, it is necessary to use excimer laser with shorter wavelength than the UV laser. We are developing the processing of organic build-up film by 248 nm excimer laser with free spectrum operation. The organic build-up films are processed directly by the irradiation using the mask by 248 nm excimer laser. We processed using Ajinomoto build-up films (ABF) as organic material. The type of ABF was GY50. We confirmed that it is possible to process via of 3 μm in build-up film and the DOF can be increased depending on the process conditions. We will report on the processability of build-up film using 248 nm excimer laser.

Purpose Noncontrast 4D-MR-angiography (MRA) using arterial spin labeling (ASL) is beneficial because high spatial and temporal resolution can be achieved. However, ASL requires acquisition of labeled and control images for each phase. The purpose of this study is to present a new accelerated 4D-MRA approach that requires only a single control acquisition, achieving similar image quality in approximately half the scan time. Methods In a multi-phase Look-Locker sequence, the first phase was used as the control image and the labeling pulse was applied before the second phase. By acquiring the control and labeled images within a single Look-Locker cycle, 4D-MRA was generated in nearly half the scan time of conventional ASL. However, this approach potentially could be more sensitive to off-resonance and magnetization transfer (MT) effects. To counter this, careful optimizations of the labeling pulse were performed by Bloch simulations. In in-vivo studies arterial visualization was compared between the new and conventional ASL approaches. Results Optimization of the labeling pulse successfully minimized off-resonance effects. Qualitative assessment showed that residual MT effects did not degrade visualization of the peripheral arteries. Conclusion This study demonstrated that the proposed approach achieved similar image quality as conventional ASL-MRA approaches in just over half the scan time. Magn Reson Med 79:224–233, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

We evaluated 3D pseudo-continuous arterial spin labeling (pCASL) using turbo spin echo with a pseudo-steady-state (PSS) readout in comparison with the other major readout methods of 3D spiral and 2D echo-planar imaging (EPI). 3D-PSS produced cerebral blood flow (CBF) values well correlated to those of the 3D spiral readout. By visual evaluation, the image quality of 3D-PSS pCASL was superior to that of 2D-EPI. The 3D-PSS technique was suggested useful as pCASL readout.

The material processing by DUV laser region has been required for wide band gap material and precise hole and groove in DUV region. It is still very hard to get high power solid-state lasers in this spectral region especially below 300 nm. The rare-gas halide excimer lasers are only the solution, and now the time has come to examine the new applications of material processing with DUV excimer lasers. We have developed several types of DUV excimer lasers. One of them is a high power 248 nm excimer laser with free spectrum operation. The 248 nm excimer laser can be applied to the process of organic materials for semiconductor packages. We are developing the processing of organic materials by 248 nm excimer laser. The organic materials are processed directly by the irradiation using the mask by 248 nm excimer laser. In this method, it is possible to process fine patterns and various patterns. We processed using Ajinomoto build-up films (ABF) as organic material. The types of ABF were GX92, GX-T31 and GY50, and their thickness was 10 μm. We confirmed that it is possible to process via of 5 μm or less in build-up film. Furthermore, it was confirmed that the L/S pattern can be processed. We will report the result of processing organic materials with 248 nm excimer laser.

The electrical properties of poly-Si thin films doped using KrF excimer laser irradiation with a phosphoric-acid coating were investigated. After laser doping, the mobility, carrier concentration, activation ratio, and contact resistivity of the poly-Si were found to be 61 cm2 /Vs, 1.5×1018 cm-3 , 18.1 %, and 8.5 × 10−5 Ω⋅cm2 , respectively. Additionally, the operation of a bottom gate transistor fabricated using laser doping was realized and is described herein.

Autonomous vehicles will bring tremendous benefits to society. However, it is expected to take a considerable period of time for their spread, and during the transition period, autonomous and manually-driven vehicles will share the same roads. Under such situations, the driving behavior of autonomous vehicles will influence manual drivers, for example, manually-driven vehicles may be stuck behind the autonomous vehicles and overtake them frequently if autonomous vehicles drive slowly for safety. In this paper, we investigate how the traffic flow and driving stress vary with autonomous vehicles by microscopic traffic simulation. We develop a microscopic traffic simulator that can reproduce traffic flow with autonomous vehicles and manually-driven vehicles. The behavior of these vehicles can be modeled by the combination of Intelligent-Driver Model (IDM) and Lane change Model with Relaxation and Synchronization (LMRS). These models can express various driver characteristics through simulation parameters such as driving speed and distance between vehicles (net distance), and we are able to create realistic scenarios like overtaking autonomous vehicles by manually-driven vehicles with faster speed than the legal speed. From the simulation results, we found that there is a desirable combination of speed and time headway that achieves both smooth traffic and less stress of drivers with a given percentage of autonomous vehicles.

In this paper, we report on the characterization of Si thin films doped by wet-chemical laser processing. Using this method, implantation and dopant activation can be performed simultaneously. After laser doping, the mobility, carrier concentration, and resistivity of the films were 74 cm2/V·s, 5.5 × 1017 cm−3, and 0.15 Ω·cm, respectively.

Moore's law has almost reached the limit of resolution on semiconductor die and, therefore, multidie packaging is one of the alternative solutions. Substrate materials currently use organic build-up films and silicon substrates [through silicon via (TSV)] in applications. But recently, organic films, too, have reached the resolution limit, and TSV is expensive. In this situation, nonalkali glass (glass) and fused silica (SiO2) substrates are expected to be good alternatives in high-frequency signal transfer applications like 5G telecommunication. But the via holes are hard to process with less defects (tips and cracks) on the glass and SiO2 substrates. Deep ultraviolet (DUV) excimer laser ablation is expected to have a finer (

We characterize poly-Si thin films doped by KrF excimer laser irradiation with a phosphoric-acid coating. In this method, implantation and dopant activation can be performed simultaneously without damage of the poly-Si crystallization. After the laser doping, the mobility, carrier concentration, activation ratio, and resistivity of poly-Si were 61 cm2/Vs, 1.5×1018 cm−3, 14.6 %, and 0.08 Ω.cm, respectively.

In this paper, we report on super low temperature doping of phosphorus to poly-Si thin films using XeF excimer laser irradiation in a phosphoric acid solution. In this method, the implantation of P atoms and dopant activation can be performed simultaneously. We prepared poly-Si films with a thickness of 50 nm, and these films were crystallized using XeF excimer laser annealing. After laser doping, the concentration of P atoms in the poly-Si films was approximately 3.5 × 1018 cm−3, and the resistance of the poly-Si films decreased by approximately 0.003 times as compared with that before laser doping.

We have succeeded in fabricating zinc oxide (ZnO) microsphere by laser ablation in the air and demonstrated ultraviolet whispering gallery mode lasing from an optically pumped ZnO microsphere. However, fabricated microspheres could not be controlled in size, and ejection direction of microsphere was random, because the generation mechanism was attributed to the droplet ejection by laser ablation. In this report, the effect of pulse duration on microsphere generation was investigated, and we introduced optical vortex to control the size and the ejection direction of droplets. The behavior of ablated target was visualized using a high-speed camera. As a result of time-resolved observation, it was found that many ZnO microspheres can be efficiency generated by the long pulse laser irradiation. In addition, it was observed that droplets were scattered randomly by Gaussian beam irradiation. In the case of optical vortex irradiation, straight flight of the droplet was achieved. Furthermore, the size of droplets changed with pulse energy and ablation spot size with optical vortex. From these results, controlled fabrication of ZnO microspheres is expected with optical vortex laser ablation.

We propose an innovative method for aluminum doping of 4H-SiC with passivation films, induced by XeF excimer laser irradiation in AlCl3 aqueous solution (28.6 wt%). A 100-nm thick Si passivation film was deposited on an n-type 4H-SiC substrate by physical vapor deposition. Using a laser beam (200 μm × 170 μm) with an irradiation fluence of 0.5–5.0 J/cm 2 , 1–300 shots were administered. After laser irradiation of 1.0 J/cm 2 and 300 shots, an Al-Si-O compound film was formed on the SiC surface. The compound film was removed by chemical wet etching and plasma treatment. After the removal of the compound film, no irradiation damage was observed on the SiC surface. From the results of secondary ion mass spectrometry measurements, high concentration aluminum doping (about 1 × 10 20 /cm 3 at the surface) was confirmed. The I-V characteristics of the junction between the n-type substrate and the irradiation area indicated clear rectification with a large on/off ratio of 9 decades in the range of ±10 V. When forward biased, electroluminescence phenomenon with a peak at 387 nm, corresponding to the electroluminescence of SiC’s band gap, was confirmed. These results prove the achievement of Al doping of n-type SiC to p-type using laser irradiation without any damage to the SiC surface.

A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement.

Laser machining is required for material processing in deep ultra violet region where the wavelength is less than 300 nm. However it is hard to get high power solid-state lasers in this spectral region. In this study, we investigated process capabilities with ArF and KrF excimer lasers to explore its possibilities for micromachining on wide bandgap materials. These results were observed with three types of microscopies. We have successfully drilled 100 micron meter holes with aspect ratio of 5 into a typical tempered glass sheet without any significant defects. As the ablation rate was quite affordable, excimer lasers are expected to be put into practical use for mass production.Laser machining is required for material processing in deep ultra violet region where the wavelength is less than 300 nm. However it is hard to get high power solid-state lasers in this spectral region. In this study, we investigated process capabilities with ArF and KrF excimer lasers to explore its possibilities for micromachining on wide bandgap materials. These results were observed with three types of microscopies. We have successfully drilled 100 micron meter holes with aspect ratio of 5 into a typical tempered glass sheet without any significant defects. As the ablation rate was quite affordable, excimer lasers are expected to be put into practical use for mass production.

RecQ-mediated genome instability 1 (RMI1) has been identified as a novel energy homeostasis-related molecule. While recent studies have suggested that change in RMI1 expression levels in adipose tissue may affect the body's energy balance, no reports have identified the mechanism behind this expression regulation. In the present study, we found that RMI1 expression increased on differentiation of 3T3-L1 fibroblasts to adipocytes. In addition, glucose stimulation induced RMI1 expression to approximately eight times the baseline level. Further, knockdown of either E2F5 or E2F8 mRNA using siRNA suppressed this glucose-induced up-regulation of RMI1 expression. These results suggest that RMI1 expression may be regulated by glucose, at least in part, via E2F expression.

The escalating prevalence of obesity is one of the most pressing health concerns of the modern era, yet existing medicines to combat this global pandemic are disappointingly limited in terms of safety and effectiveness. The inadequacy of currently available therapies for obesity has made new drug development crucial. In the past several decades, however, major progress has been achieved in understanding adipocyte hyperplasia associated with the pathogenesis of obesity, and consequently new potential targets for the medical treatment of obesity have been identified. We primarily review recent progress in the regulation of adipocyte hyperplasia as a novel emerging nontraditional approach. In this minireview, we focus on recQ-mediated genome instability 1 (RMI1), a recently identified novel molecular target for obesity treatment. RMI1-deficient mice have been found to be resistant to high-fat diet- and genetics-related obesity. Expression of this protein is regulated by E2F transcription factors, and recent studies have suggested that RMI1 plays an important role in the control of energy homeostasis during the development of obesity, with a mode of action based on the regulation of adipocyte hyperplasia.

Lipid phosphatase SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2) plays an important role in the regulation of insulin signaling. In this report, we identified AS1938909, a novel small-molecule SHIP2 inhibitor. AS1938909 showed potent inhibition of SHIP2 (Ki = 0.44 μM) and significant selectivity over other related phosphatases. Further, AS1938909 increased Akt phosphorylation, glucose consumption, and glucose uptake in L6 myotubes. Treatment of L6 myotubes with SHIP2 inhibitors for 48 h significantly induced expression of GLUT1 mRNA, but not that of GLUT4. These results suggest that pharmacological inhibition of SHIP2 activates glucose metabolism due, at least in part, to up-regulation of GLUT1 gene expression.

Inositol polyphosphate 5-phosphatase (SHIP2) is an important negative regulator of intracellular phosphatidylinositol phosphate, a key second messenger of various intracellular signaling pathways. The functional upregulation of SHIP2 results in signaling blockade, leading to related disorders.We first summarize the role of SHIP2 in the regulation of insulin signaling and type 2 diabetes, including remarkable advances in pharmacological approaches. In addition, this review highlights new findings regarding the involvement of SHIP2 in a number of diseases, including cancer, neurodegenerative diseases, and atherosclerosis.Recently identified small-molecule inhibitors of SHIP2 phosphatase activity emphasize the potential therapeutic value of SHIP2. In addition, currently available evidence demonstrates the importance of the scaffolding-type protein function of SHIP2. Understanding this interesting function will help clarify the complicated involvement of SHIP2 in various disorders.Recent studies have demonstrated that SHIP2 is a promising therapeutic target for not only type 2 diabetes, but also cancer, neurodegenerative diseases, and atherosclerosis. Targeting SHIP2 through specific small-molecule inhibitors will have beneficial effects on these diseases.

The aim of this study is to discover and characterize novel energy homeostasis-related molecules. We screened stock mouse embryonic stem cells established using the exchangeable gene trap method, and examined the effects of deficiency of the target gene on diet and genetic-induced obesity. The mutant strain 0283, which has an insertion at the recQ-mediated genome instability 1 (RMI1) locus, possesses a number of striking features that allow it to resist metabolic abnormalities. Reduced RMI1 expression, lower fasting-blood glucose and a reduced body weight (normal diet) were observed in the mutant mice. When fed a high-fat diet, the mutant mice were resistant to obesity, and also showed improved glucose intolerance and reduced abdominal fat tissue mass and food intake. In addition, the mutants were also resistant to obesity induced by the lethal yellow agouti (Ay) gene. Endogenous RMI1 genes were found to be up-regulated in the liver and adipose tissue of KK-Ay mice. RMI1 is a component of the Bloom’s syndrome gene helicase complex that maintains genome integrity and activates cell-cycle checkpoint machinery. Interestingly, diet-induced expression of E2F8 mRNA, which is an important cell cycle-related molecule, was suppressed in the mutant mice. These results suggest that the regulation of energy balance by RMI1 is attributable to the regulation of food intake and E2F8 expression in adipose tissue. Taken together, these findings demonstrate that RMI1 is a novel molecule that regulates energy homeostasis.

The reactivities to individual U1 small nuclear ribonucleoprotein (snRNP) components and their relationship to clinical features in patients with anti-U1 snRNP antibodies were examined. We evaluated 114 patients with connective tissue disease whose sera were positive for anti-U1 snRNP antibodies, but negative for anti-Sm antibodies. Antibodies to the U1 snRNP polypeptides 70K, A, and C were detected using subunit-specific enzyme-linked immunosorbent assays and antibodies to U1 small nuclear RNA (snRNA) were identified by an immunoprecipitation assay using deproteinized HeLa cell extracts. The clinical features were retrospectively obtained by chart review and prospectively collected after study entry. The pattern of antibody reactivities to U1 snRNP components varied among patients. The frequency of anti-70K, anti-A, anti-C, and anti-U1 snRNA antibodies was 60%, 86%, 74%, and 46%, respectively. There was no relationship between each reactivity and the clinical findings, but the presence of reactivities to increasing numbers of U1 snRNP components was correlated with sclerodactyly, shortness of the sublingual frenulum, esophageal dysfunction, and a lack of persistent proteinurea (p < 0.05 for all comparisons). The detection of autoantibody reactivities to individual components of the U1 snRNP particle is potentially useful for predicting the clinical course in patients with connective tissue disease and anti-U1 snRNP antibodies. Lupus (2010) 19, 307—312.

Background and purpose: The lipid phosphatase known as SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2) plays an important role in the regulation of the intracellular insulin signalling pathway. Recent studies have suggested that inhibition of SHIP2 could produce significant benefits in treatment of type 2 diabetes. However, there were no small molecule SHIP2 inhibitors and we, therefore, aimed to identify this type of compound.

We have developed a sequence for abdominal examination that fat suppressed 3D-T1W by a linear filling order using an adiabatic pulse for frequency selective fat suppression. We simulated the change in fat signal using a linear method and checked the starting point of data filling for the null point using a phantom of different T1 values. We then checked the contrast between the fat signal and liver. After checking by using simulation, a clinical evaluation was done. The change in fat signal was mostly the same after the fourth shot, and we were able to estimate the null point of the fat signal by the following parameters: TR, FA, TFE factor, and shot interval. Consequently, we could control the starting point of data filling in k-space for fat suppression. The contrast between fat and liver was improved because noise was reduced by the linear method. The sequence developed with the linear filling order using frequency selective fat suppression pulse proved to be useful.

Autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and autoimmune diabetes are characterized by the production of autoantibodies that serve as useful diagnostic markers, surrogate markers, and prognostic factors. We devised an in vitro system to detect these clinically pivotal autoantibodies using a photoimmobilized autoantigen microarray. Photoimmobilization was useful for preparing the autoantigen microarray, where autoantigens are covalently immobilized on a plate, because it does not require specific functional groups of the autoantigens and any organic material can be immobilized by a radical reaction induced by photoirradiation. Here, we prepared the microarray using a very convenient method. Aqueous solutions of each autoantigen were mixed with a polymer of poly(ethylene glycol) methacrylate and a photoreactive crosslinker, and the mixtures were microspotted on a plate and dried in air. Finally, the plate was irradiated with an ultraviolet lamp to obtain immobilization. In the assay, patient serum was added to the microarray plate. Antigen-specific IgG adsorbed on the microspotted autoantigen was detected by peroxidase-conjugated anti-IgG antibody. The chemical luminescence intensities of the substrate decomposed by the peroxidase were detected with a sensitive CCD camera. All autoantigens were immobilized stably by this method and used to screen antigen-specific IgG. In addition, the plate was covered with a polydimethylsiloxane sheet containing microchannels and automated measurement was carried out.

A 45 year-old Japanese woman developed numbness and tingling of both hands and feet. Electrophysiological examination revealed sensorimotor polyneuropathy. She was diagnosed as suffering from sarcoidosis on the basis of the pathological findings from dermal biopsy. Steroid therapy effectively improved the clinical symptoms. Although sarcoid neuropathy is rare, this case suggests sensorimotor polyneuropathy is an important symptom of sarcoidosis and can represent the initial clinical manifestation of the disease.

ステロイド薬は,強力な抗炎症作用,免疫抑制作用を有し,膠原病の種々の病態に対する基本的な治療薬である.ステロイド薬にはいろいろな種類があり,各薬剤の作用時間,薬理作用などの特徴から,症状,病態にあわせて,これらを使い分ける必要がある.また,投与量,投与方法を工夫し,必要量を最短期間用いることで,最大の効果を引き出し,副作用を最小限に抑えることが可能となる.実践的なステロイド薬の使用法をまとめた.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the occurrence of numerous autoantibodies directed against nuclear antigens. Anti-histone antibodies (AHA) are as prevalent as their anti-dsDNA counterparts in SLE. Despite their frequency and potential importance, there have not been given much attention to AHA until recently. Nucleosomes, the fundamental repeating units of the chromatin, are formed of complexes of histones and DNA. The nucleosome core particle is composed of a central tetramer of 2 molecules each of H3 and H4 flanked by 2 dimers of H2A and H2B and surrounded by 2 superhelical turns of approximately 146 base pairs of DNA. The full nucleosome contains a molecule of H1 located at the point where DNA enters and exits the nucleosome. Recent studies have shown that the post transcriptional modification of histone changes chromatin structure to regulate transcription and the concept of this mechanism "epigenetics" has become center of attention in the field of basic cell biology. There have been described diverging specificities of AHA. Many attempts to locate antigenic determinants recognized by AHA have been made and H1 and H2B have been thought as common targets in lupus patients. Studies on murine models of lupus have shown several interesting findings. The universal epitope is located on H2B in (NZBxNZW)F1 mice. In addition to core histones, MRL-MP/Fas(lpr) mice develop high titers of autoantibodies to H1. Autoimmunity to chromatin regularly involves humoral immune responses directed against H1. These histones appear to be an early (possibly initial trigger) autoantigen for this autoimmune response in lupus.

We describe the case of a 41-year-old woman with systemic lupus erythematosus (SLE) who suffered from repeated reversible lupus enteritis characterized by marked edematous thickening of the small intestine. Ultrasonography (US) and computed tomography (CT) manifested as an 'accordion-like appearance' and a 'target-like appearance', respectively. Resolution of gastrointestinal tract wall thickening was observed on follow-up US performed a week after the increase in predinosolone (PSL). We conclude that careful evaluation of sonographic and radiographic findings helps to establish the diagnosis of lupus enteritis.

SUMMARYWe have reported previously that p95c, a novel 95-kDa cytosolic protein, was the target of autoantibodies in sera of patients with autoimmune hepatic diseases. We studied 30 sera that were shown previously to immunoprecipitate a 95 kDa protein from [35S]-methionine-labelled HeLa lysates and had a specific precipitin band in immunodiffusion. Thirteen sera were available to test the ability of p95c antibodies to inhibit nuclear envelope assembly in an in vitro assay in which confocal fluorescence microscopy was also used to identify the stages at which nuclear assembly was inhibited. The percentage inhibition of nuclear envelope assembly of the 13 sera ranged from 7% to 99% and nuclear envelope assembly and the swelling of nucleus was inhibited at several stages. The percentage inhibition of nuclear assembly was correlated with the titre of anti-p95c as determined by immunodiffusion. To confirm the identity of this autoantigen, we used a full-length cDNA of the p97/valosin-containing protein (VCP) to produce a radiolabelled recombinant protein that was then used in an immunoprecipitation (IP) assay. Our study demonstrated that 12 of the 13 (93%) human sera with antibodies to p95c immunoprecipitated recombinant p97/VCP. Because p95c and p97 have similar molecular masses and cell localization, and because the majority of sera bind recombinant p97/VCP and anti-p95c antibodies inhibit nuclear assembly, this is compelling evidence that p95c and p97/VCP are identical.

ERK is activated by soluble growth factors in adherent cells. However, activation of ERK is barely detectable and not sufficient for cell proliferation in non-adherent cells. Here, we show that exogenous expression of vinexin beta, a novel focal adhesion protein, allows anchorage-independent ERK2 activation stimulated by epidermal growth factor. In contrast, expression of vinexin beta had no effect on ERK2 activation in adherent cells, suggesting that vinexin beta regulates the anchorage dependence of ERK2 activation. Analyses using deletion mutants demonstrated that a linker region between the second and third SH3 domains of vinexin beta, but not the SH3 domains, is required for this function of vinexin beta. To evaluate the pathway regulating the anchorage dependence of ERK2 activation, we used a dominant-negative mutant of p21-activated kinase (PAK) and a specific inhibitor (H89) of cAMP-dependent protein kinase (PKA) because PAK and PKA are known to regulate the anchorage dependence of ERK2 activation. The dominant-negative mutant of PAK suppressed the anchorage-independent ERK2 activation induced by expression of vinexin beta. The dominant-negative mutant of vinexin beta inhibited the anchorage-independent ERK2 activation induced by the PKA inhibitor. Together, these observations indicate that vinexin beta plays a key role in regulating the anchorage dependence of ERK2 activation through PKA-PAK signaling.

Objective. To determine cytokines and MHC class II alleles in Japanese patients with adult Still's disease (ASD) and clarify the association between those profiles and chronic articular disease. Methods. Of 35 patients with ASD (13 men, 22 women, mean age at onset 34.0 yr), 17 (49%) had chronic arthritis (>6 months, chronic articular ASD) and 18 (51%) lacked chronic arthritis (systemic ASD). Cytokines and cytokine receptors in sera were measured by ELISA. Correlations of each cytokine with disease activity or C-reactive protein (CRP) were determined. MHC class II alleles were examined by polymerase chain reaction methods. Results. In chronic articular ASD, female gender was more frequent and liver dysfunction and myalgia were rarer than in systemic ASD. In active disease, the white blood cell count was lower, but total IgG was greater in patients with chronic articular ASD than in those with systemic ASD. Tumour necrosis factor (TNF) α, soluble TNF receptor 2 and interleukin (IL)-18 were increased in both types of ASD, even in remission. Soluble IL-2 receptors, IL-4 and IL-18 levels were correlated with disease activity or CRP value only in chronic articular ASD. Interferon γ and IL-8 remained increased only in chronic articular ASD, even when disease activity, including IL-6 and CRP, was low. DRB1 * 1501 (DR2) and DRB1 * 1201 (DR5) alleles were more frequent in chronic articular than in systemic ASD, whereas DQB1 * 0602 (DQ1) was frequently observed in both types of ASD. Conclusion. The present study suggests that ASD with chronic articular disease has distinct clinical, cytokine and immunogenetic profiles.

Systemic autoimmune diseases that are resistant to conventional treatment cause considerable morbidity and mortality. Although aggressive new approaches to treating autoimmune diseases have been developed over the past decade, there are still patients with a severe, progressive, and life-threatening course. Based on animal studies and experience in the treatment of hematological disorders with preexisting autoimmune disease, hematopoietic stem cell transplantation has been proposed for the treatment of severe autoimmune diseases. Immunoablation and subsequent autologous peripheral blood stem cell transplantation using CD34(+) hematopoietic cells with T cell depletion have been used for selected severe autoimmune diseases at many institutes in Australia, Europe, and the United States. However, it is necessary to assess the efficacy and safety of this therapy compared with conventional and other newly emerging therapies.